Clinical Trials Register

Summary
EudraCT Number:	2018-000610-38
Sponsor's Protocol Code Number:	CPDR001J2201
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-06-21
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2018-000610-38

A.3

Full title of the trial

A randomized, open-label, phase II open platform study evaluating the efficacy and safety of novel spartalizumab (PDR001) combinations in previously treated unresectable or metastatic melanoma

Estudio de fase II, aleatorizado, abierto, de grupos abiertos en el que se evalúa la eficacia y la seguridad de nuevas combinaciones de spartalizumab (PDR001) en melanoma irresecable o metastásico previamente tratado

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to evaluate the efficacy and safety of novel spartalizumab combinations in patients with previously treated unresectable or metastatic melanoma

Estudio que se evalúa la eficacia y la seguridad de nuevas combinaciones de spartalizumab en melanoma irresecable o metastásico previamente tratado

A.4.1

Sponsor's protocol code number

CPDR001J2201

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Farmacéutica, S.A.
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farmacéutica, S.A.
B.5.2	Functional name of contact point	Trial Monitoring Organization (TMo)
B.5.3	Address:
B.5.3.1	Street Address	Gran Vía de les Corts Catalanes, 764
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08013
B.5.3.4	Country	Spain
B.5.4	Telephone number	+3493 3064464
B.5.5	Fax number	NA
B.5.6	E-mail	eecc.novartis@novartis.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	spartalizumab
D.3.2	Product code	PDR001
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	spartalizumab
D.3.9.2	Current sponsor code	PDR001
D.3.9.4	EV Substance Code	SUB171710
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	capmatinib
D.3.2	Product code	INC280
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	capmatinib
D.3.9.2	Current sponsor code	INC280
D.3.9.4	EV Substance Code	SUB31645
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	LAG525
D.3.2	Product code	LAG525
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not yet defined
D.3.9.2	Current sponsor code	LAG525
D.3.9.4	EV Substance Code	SUB177020
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	ILARIS
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Ltd
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	ACZ885
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	canakinumab
D.3.9.1	CAS number	914613-48-2
D.3.9.2	Current sponsor code	ACZ885
D.3.9.4	EV Substance Code	SUB30137
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 5
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	capmatinib
D.3.2	Product code	INC280
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	capmatinib
D.3.9.2	Current sponsor code	INC280
D.3.9.4	EV Substance Code	SUB31645
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Unresectable or metastatic melanoma

Melanoma metastásico o irresecable

E.1.1.1

Medical condition in easily understood language

Unresectable or metastatic melanoma

Melanoma metastásico o irresecable

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10027481
E.1.2	Term	Metastatic melanoma
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of each combination arm, as measured by objective response rate (ORR)

Evaluar la eficacia de cada grupo de combinación, según la tasa de respuesta objetiva (TRO) confirmada

E.2.2

Secondary objectives of the trial

Key secondary:
To evaluate the efficacy of each combination arm in terms of duration of response (DoR)

Other secondary objectives :
- To evaluate the efficacy of each combination arm in terms of progression-free survival (PFS) and disease control rate (DCR)
-To evaluate the overall survival (OS) of each combination arm
-To characterize the safety and tolerability of each combination arm
-To characterize the prevalence and incidence of immunogenicity of spartalizumab, LAG525 and canakinumab in each combination arm
-To evaluate changes in levels and phenotype of T cell populations in the tumor and tumor microenvironment after treatment with combination therapies

Secundario clave: Evaluar la eficacia de cada grupo de combinación en términos de duración de respuesta (DR)
-Evaluar la eficacia de cada grupo de combinación, según la supervivencia libre de progresión (SLP) y la tasa de control de la enfermedad (TCE)
-Evaluar la supervivencia global (SG) de cada grupo de combinación
-Caracterizar la seguridad y tolerabilidad de cada grupo de combinación.
-Caracterizar la prevalencia e incidencia de inmunogenicidad de spartalizumab, LAG525 y canakinumab en cada grupo de combinación.
- Evaluar los cambios en los niveles y fenotipo de las poblaciones de las células T y en el microambiente tumoral después del tratamiento con las terapias combinadas.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV melanoma using AJCC edition 8
• Previously treated for unresectable or metastatic melanoma. Subjects must have at least received the following treatments:
-V600BRAF wild-type patients: must have received anti-PD-1/PD-L1 single-agent, or in combination with anti-CTLA-4 therapy
-V600BRAF mutant patients: must have received prior anti-PD-1/PD-L1 single-agent, or in combination with anti-CTLA-4 therapy. In addition, subjects must have received prior V600BRAF inhibitor therapy, either single-agent or in combination with a MEK inhibitor
• ECOG performance status 0-2
• At least one measurable lesion per RECIST v1.1
• At least one lesion, suitable for sequential mandatory tumor biopsies (screening and on-treatment) in accordance with the biopsy guidelines specified in protocol. The same lesion must be biopsied sequentially.
• Screening tumor biopsy must fulfill the tissue quality criteria outlined in the protocol, as assessed by a local pathologist

Other inclusion criteria may apply.

Los criterios de inclusión principales se indican a continuación; véase en el protocolo el listado completo de los criterios de inclusión:
-Melanoma irresecable o metastásico en estadio IIIB/C/D o IV histológicamente confirmado según AJCC edición 8.
-Tratamiento previo para melanoma irresecable o metastásico. Los sujetos deben haber recibido al menos los siguientes tratamientos.
- Los pacientes con V600BRAF no mutado deben haber recibido anti-PD-1/PD-L1 en monoterapia o en combinación con un tratamiento anti-CTLA-4.
-Los pacientes con V600BRAF mutado deben haber recibido tratamiento previo con anti-PD-1/PD-L1 en monoterapia o en combinación con un tratamiento anti-CTLA-4. Asimismo, los sujetos deben haber recibido tratamiento previo con un inhibidor V600BRAF, bien en monoterapia o en combinación con un inhibidor MEK.
-Estado funcional ECOG 0-2
- Al menos una lesión medible según RECIST v1.1.
- Al menos una lesión apta para biopsias tumorales obligatorias secuenciales (selección y durante el tratamiento) según las pautas para biopsias especificadas en el protocolo. Se deben haber realizado biopsias secuenciales de la misma lesión. Nota: esta lesión no puede utilizarse como lesión diana.
-La biopsia tumoral realizada en la selección debe cumplir los criterios de calidad del tejido descritos en el protocolo, según la evaluación de un patólogo local.

Otros criterios de inclusión pueden aplicar

E.4

Principal exclusion criteria

• Subjects with uveal or mucosal melanoma
• Presence of clinically active or unstable brain metastasis. Note: Subjects with unstable brain lesions who have been definitively treated with stereotactic radiation therapy, surgery or gamma knife therapy are eligible.
- Subjects with brain lesions who are untreated (i.e. newly discovered brain lesions during screening) or received whole brain radiation must have documented stable disease as assessed by two consecutive assessments ≥ 4 weeks apart and have not required steroids for at least ≥ 4 weeks prior to enrollment.
• Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.
• Active infection requiring systemic antibiotic therapy.
• Systemic chronic steroid therapy (> 10mg/day prednisone or equivalent) or any other immunosuppressive therapy 7 days prior to planned date of first dose of study treatment. Note: Local steroids such as topical, inhaled, nasal and
ophthalmic steroids are allowed.
• Active, known or suspected autoimmune disease or a documented history of autoimmune disease. Note:
Subjects with vitiligo, controlled type I diabetes mellitus on stable insulin dose, residual autoimmunerelated
hypothyroidism only requiring hormone replacement or psoriasis not requiring systemic treatment are permitted.
• Prior allogenic bone marrow or solid organ transplant
• History of known hypersensitivity to any of the investigational drugs used in this study

Other exclusion criteria may apply.

Los criterios de exclusión principales comunes a todos los grupos de combinación se indican a continuación; véase en el protocolo el listado completo de los criterios de exclusión comunes y específicos de cada grupo:
-Sujetos con melanoma uveal o de la mucosa.
- Presencia de metástasis cerebral clínicamente activa o inestable. Nota: los sujetos con lesiones cerebrales inestables que hayan recibido tratamiento definitivo con radioterapia estereostática, cirugía o tratamiento con cuchillo gamma son elegibles.
- Sujetos con lesiones cerebrales no tratadas (p. ej., lesiones cerebrales recién descubiertas durante la selección) o que hayan recibido radiación del cerebro completo deben tener una enfermedad estable documentada medida mediante dos evaluaciones consecutivas con ≥ 4 semanas de diferencia y que no haya requerido esteroides durante ≥ 4 semanas antes del reclutamiento.
- Uso de vacunas vivas contra enfermedades infecciosas durante las 4 semanas anteriores al comienzo del tratamiento del estudio.
- Infección activa que requiera tratamiento antibiótico sistémico.
- Tratamiento crónico con esteroides sistémicos (> 10 mg/día de prednisona o equivalente) o cualquier otro tratamiento inmunosupresor durante los 7 días anteriores a la fecha prevista de la primera dosis del tratamiento del estudio. Nota: se permite el uso de esteroides tópicos, inhalados, nasales y oftalmológicos locales.
- Enfermedad autoinmune activa, conocida o sospechada, o antecedentes documentados de enfermedad autoinmune. Nota: está permitida la inclusión de sujetos con vitíligo, diabetes mellitus de tipo I controlada con una dosis de insulina estable, hipotiroidismo autoinmune residual que solo requiera terapia hormonal sustitutiva, o psoriasis que no requiera tratamiento sistémico.
- Trasplante previo alogénico de médula ósea o de órganos sólidos.
- Antecedentes de hipersensibilidad conocida a alguno de los fármacos en investigación utilizados en este estudio.

E.5 End points

E.5.1

Primary end point(s)

Overall Response Rate (ORR) defined as the proportion of patients with a best overall response of either confirmed complete response or confirmed partial response (as per local review and according to RECIST v1.1)

Tasa de respuesta objetiva (TRO) confirmada definida como el porcentaje de pacientes con una mejor respuesta confirmada de respuesta completa o respuesta parcial (por revisión local y de acuerdo con los criterios RECIST 1.1)

E.5.1.1

Timepoint(s) of evaluation of this end point

28 months

28 meses

E.5.2

Secondary end point(s)

- Duration of Response (DOR) defined as the time from date of first documented complete response or partial response to date of first documented disease progression or death due to any cause (as per local review and according to RECIST v1.1)
- Overall Survival (OS) defined as time from date of randomization to date of death due to any cause
- Progression Free Survival (PFS) defined as the interval of time between the date of randomization to the date of event defined as the first documented disease progression or death due to any cause (as per local review and according to RECIST v1.1)
- Disease Control Rate (DCR) defined as the proportion of patients with best overall response of complete response, partial response, or stable disease (as per local review and according to RECIST v1.1)
- Prevalence of anti-drug antibodies (ADA) at baseline: number of patients with presence of ADA
- Incidence of anti-drug antibodies (ADA): number of patients developing new ADA
- Percentage of subjects with a favorable biomarker profile (pFBP) defined by changes in number of cells expressing the CD8+ T cell marker and/or T cell activation marker(s), T cell clonality and/or gene expression tumor biosy samples.

-Duración de respuesta (DR) definida como el tiempo desde la fecha documentada de la primera respuesta completa o respuesta parcial hasta la fecha documentada de la progresión de la enfermedad o muerte por cualquier causa (por revisión local y de acuerdo con los criterios RECIST 1.1)
-Supervivencia global (SG) definida como el tiempo transcurrido desde la randomización hasta la muerte por cualquier causa.
-Supervivencia libre de progresión (SLP) definida como el intervalo entre la fecha de randomización y la fecha de la primera progresión documentada de la enfermedad o muerte por cualquier causa (por revisión local y de acuerdo con los criterios RECIST 1.1)
-Tasa de control de la enfermedad (TCE) definida como de pacientes con una mejor respuesta de respuesta completa, respuesta parcial o enfermedad estable (por revisión local y de acuerdo con los criterios RECIST 1.1)
-Prevalencia de anticuerpos contra el fármaco (ADA) en la visita basal: Número de pacientes con presencia de ADA en la visita basal
-Incidencia de ADA: número de pacientes que desarrollan nuevos ADA durante el tratamiento
-Porcentaje de sujetos pacientes con un perfil favorable de biomarcadores (pFBP) definido por los cambios en el número de células que expresen el marcador de células T CD8+ y/o el marcador de activación de células T, clones de células T y/o expresión génica en las biopsias de tumor.

E.5.2.1

Timepoint(s) of evaluation of this end point

- DOR: Up to disease progression or death due to any cause, whichever occurs first (3 years)
- OS: Up to death due to any cause (3 years)
- PFS: Up to disease progression or death due to any cause, whichever occurs first (3 years)
- DCR: Up to disease progression or death due to any cause, whichever occurs first (3 years)
- Prevalence of ADA prevalence at baseline: at baseline
- Incidence of ADA: Throughout study until 150 day after last drug administration
- pFBP: Baseline and after 3-4 weeks on treatment

-DR: Hasta la progresión de la enfermedad o la muerte por cualquier causa, lo que ocurra primero (3 años).
-SG: Hasta la muerte por cualquier causa (3 años)
-SLP: hasta progresión de la enfermedad o muerte por cualquier causa, lo que ocurra primero (3 años).
-TCE: Hasta la progresión de la enfermedad o muerte por cualquier causa, lo que ocurra primero (3 años).
-Prevalencia de ADA al inicio del estudio: al inicio del studio
- Incidencia de ADA: durante todo el estudio hasta 150 días después de la última administración de la medicación.
- Perfil favorable de biomarcadores (pFBP) al inicio y a las 3-4 semanas de tratamiento

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Canada

France

Germany

Italy

Netherlands

Spain

Switzerland

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of study is defined as the earliest occurrence of one of the following:

- All patients have died or discontinued from the study
- Another clinical study becomes available that can continue to provide the appropriate combination treatment in this patient population and all patients ongoing are eligible to be transferred to that clinical study
- 52 weeks after data-cut for primary CSR.

El final del estudio tendrá lugar cuando uno de los siguientes eventos suceda,lo que ocurra primero:
Todos los pacientes mueran o sean discontinuados del estudio
Haya disponible otro estudio clínico para continuar ofreciendo el tratamiento combinado apropiado en esta población de pacientes y todos los pacientes que continúen en el ensayo sean elegibles para ser transferidos a ese estudio clínico
52 semanas después del corte de datos para la elaboración del Informe Clínico primario del estudio

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

120

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

120

F.4.2.2

In the whole clinical trial

160

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

For patients still receiving study treatment at the time of end of study, every effort will be made to continue provision of study treatment outside this study through an alternative setting to patients who in the opinion of the investigator are still deriving clinical benefit.

Para pacientes que estén recibiendo tratamiento del ensayo en el momento de fin de ensayo, se hará todo lo posible para continuar suministrando la medicación fuera del estudio , en aquellos pacientes que, en opinión del investigador, aún obtienen un beneficio clínico

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-08-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-03

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2022-12-30

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